Fig. 1: Schematic workflow: a pan-tissue human atlas of bimodal, allele-specific and parent-of-origin DNA methylation.

Using fragment-level analysis, we identified 324,759 genomic loci showing a mixture of fully methylated and fully unmethylated DNA fragments. Genetic variation at neighboring SNPs was used to split the fragments by genotype, and to identify 34,426 loci that show allele-specific methylation. These were analyzed across multiple donors and classified as sequence-dependent allele-specific methylation (SD-ASMs, bottom-left) where methylation consistently segregates with one allele, or parental allele-specific methylation (bottom-right) if both methylated and unmethylated epialleles exist, regardless of the genotype, suggesting that methylation is associated with parental, rather than genetic, origin. Overall, we identified 460 parental-ASM loci, including most known imprinted DMRs, as well as multiple novel regions. 78 of these regions are associated with imprinted genes. One such novel region within CHD7, a gene associated with CHARGE syndrome, was validated as maternally methylated. Remarkably, some of these regions also show cell-type-specific effects, including escape of allele-specific methylation.